This shared investigator R01 is an extension of 5 P01 NS043985-09. The current work builds on prior successes in developing long-acting nanoformulated antiretroviral therapies (nanoART) to improve drug delivery and therapeutic outcomes for aged virus-infected people. Elucidating the interplay between aging, HIV disease and ART is the overarching project goal. The tools are available to address this interplay which can simplify drug regimens and improve disease outcomes. First, nanoART is available for long- term testing of antiretroviral responses together with central nervous system (CNS) and broad metabolic functions. Second, interdisciplinary bioimaging, behavior, and nanopharmaceutics can evaluate virus, drug, immune, and age-related toxicities. Third, drug pharmacokinetic, pharmacodynamics, drug-drug interactions can be measured by employing PXR humanization (the androstane receptor with replacement of the mouse Cyp3a with human CYP3A4) in rodents. This can be used to evaluate long-term immune and antiviral responses. Fourth, a novel tool designed to improve ART delivery to viral reservoirs was discovered for theranostics (simultaneous diagnostics and therapeutics). This system is called small magnetite ART (or SMART) and permits assay of drug biodistribution by imaging tests. Such outcome measures would improve ART CNS and lymphoid delivery and thus combat persistent HIV-1 infection. A group of investigators with productive histories of working together was assembled. They include neuroscientists (H. Gendelman, Co- PI), immunopathologists (L. Poluektova, Co-PI), aging and cognitive behavior researchers (S. Bonasera), bioimaging experts (M. Boska) those with expertise in neurodegenerative diseases (R. L. Mosley), and experts in nanomedicine and drug delivery (X. Liu). The work is timely and relevant. Although ART has profoundly reduced morbidities and mortality for HIV infection coincident with virus reductions and immune preservation, the prevalence of neurocognitive impairments and drug toxicities remain common. Indeed, the doubling of virus-infected patients > 50 years of age is upon us. New co-morbid conditions now include cerebrovascular disease, non-AIDS malignancies, insulin resistance, hyperlipidemia, dementia, and liver, renal and bone disorders. This demands new model systems for disease studies relevant to current HIV/AIDS trends. Indeed, the work reflects the changing epidemiologic patterns of human disease. [We acknowledge that the prior submission lacked preliminary data and details about our humanized brain model and nanoformulations and response of the animals to treatments. A number of recent publications and significant new preliminary data are now included that addresses each of these concerns in a thorough and reasoned manner.] The tools that are needed to tackle relevant questions in HIV and aging are also available for study.